Sarcopenia, the degenerative loss of skeletal muscle mass, quality and strength, lacks early diagnostic tools and new therapeutic strategies to prevent the frailty-to-disability transition often responsible for the medical institutionalization of elderly individuals. Herein we report that production of the endogenous peptide apelin, induced by muscle contraction, is reduced in an age-dependent manner in humans and rodents and is positively associated with the beneficial effects of exercise in older persons. Mice deficient in either apelin or its receptor (APLNR) presented dramatic alterations in muscle function with increasing age. Various strategies that restored apelin signaling during aging further demonstrated that this peptide considerably enhanced muscle function by triggering mitochondriogenesis, autophagy and anti-inflammatory pathways in myofibers as well as enhancing the regenerative capacity by targeting muscle stem cells. Taken together, these findings revealed positive regulatory feedback between physical activity, apelin and muscle function and identified apelin both as a tool for diagnosis of early sarcopenia and as the target of an innovative pharmacological strategy to prevent age-associated muscle weakness and restore physical autonomy.

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  1. 1.

    Janssen, I., Shepard, D. S., Katzmarzyk, P. T. & Roubenoff, R. The healthcare costs of sarcopenia in the United States. J. Am. Geriatr. Soc. 52, 80–85 (2004).

  2. 2.

    Han, K. et al. Sarcopenia as a determinant of blood pressure in older Koreans: findings from the Korea National Health and Nutrition Examination Surveys (KNHANES) 2008-2010. PLoS One 9, e86902 (2014).

  3. 3.

    Anker, S. D., Morley, J. E. & von Haehling, S. Welcome to the ICD-10 code for sarcopenia. J. Cachexia Sarcopenia Muscle 7, 512–514 (2016).

  4. 4.

    Pasco, J. A. et al. Sarcopenia and the common mental disorders: a potential regulatory role of skeletal muscle on brain function? Curr. Osteoporos. Rep. 13, 351–357 (2015).

  5. 5.

    Martinez, B. P. et al. Frequency of sarcopenia and associated factors among hospitalized elderly patients. BMC Musculoskelet. Disord. 16, 108 (2015).

  6. 6.

    Robertson, D. A., Savva, G. M. & Kenny, R. A. Frailty and cognitive impairment—a review of the evidence and causal mechanisms. Ageing Res. Rev. 12, 840–851 (2013).

  7. 7.

    Rockwood, K. & Mitnitski, A. Frailty in relation to the accumulation of deficits. J. Gerontol. A Biol. Sci. Med. Sci. 62, 722–727 (2007).

  8. 8.

    Samper-Ternent, R., Al Snih, S., Raji, M. A., Markides, K. S. & Ottenbacher, K. J. Relationship between frailty and cognitive decline in older Mexican Americans. J. Am. Geriatr. Soc. 56, 1845–1852 (2008).

  9. 9.

    Giannoulis, M. G., Martin, F. C., Nair, K. S., Umpleby, A. M. & Sonksen, P. Hormone replacement therapy and physical function in healthy older men. Time to talk hormones? Endocr. Rev. 33, 314–377 (2012).

  10. 10.

    Hepple, R. T. Mitochondrial involvement and impact in aging skeletal muscle. Front. Aging Neurosci. 6, 211 (2014).

  11. 11.

    Johnson, M. L., Robinson, M. M. & Nair, K. S. Skeletal muscle aging and the mitochondrion. TEM 24, 247–256 (2013).

  12. 12.

    Cartee, G. D., Hepple, R. T., Bamman, M. M. & Zierath, J. R. Exercise promotes healthy aging of skeletal muscle. Cell Metab. 23, 1034–1047 (2016).

  13. 13.

    Ryu, D. et al. Urolithin A induces mitophagy and prolongs lifespan in C. elegans and increases muscle function in rodents. Nat. Med. 22, 879–888 (2016).

  14. 14.

    Snijders, T. et al. The skeletal muscle satellite cell response to a single bout of resistance-type exercise is delayed with aging in men. Age (Dordr.) 36, 9699 (2014).

  15. 15.

    Bernet, J. D. et al. p38 MAPK signaling underlies a cell-autonomous loss of stem cell self-renewal in skeletal muscle of aged mice. Nat. Med. 20, 265–271 (2014).

  16. 16.

    Fry, C. S. et al. Inducible depletion of satellite cells in adult, sedentary mice impairs muscle regenerative capacity without affecting sarcopenia. Nat. Med. 21, 76–80 (2015).

  17. 17.

    Castan-Laurell, I. et al. Apelin, diabetes, and obesity. Endocrine 40, 1–9 (2011).

  18. 18.

    Dray, C. et al. Apelin and APJ regulation in adipose tissue and skeletal muscle of type 2 diabetic mice and humans. Am. J. Physiol. Endocrinol. Metab. 298, E1161–E1169 (2010).

  19. 19.

    Dray, C. et al. Apelin stimulates glucose utilization in normal and obese insulin-resistant mice. Cell Metab. 8, 437–445 (2008).

  20. 20.

    Besse-Patin, A. et al. Effect of endurance training on skeletal muscle myokine expression in obese men: identification of apelin as a novel myokine. Int. J. Obes. (Lond.) 38, 707–713 (2014).

  21. 21.

    Fujie, S. et al. Reduction of arterial stiffness by exercise training is associated with increasing plasma apelin level in middle-aged and older adults. PLoS One 9, e93545 (2014).

  22. 22.

    Newman, A. B. et al. Sarcopenia: alternative definitions and associations with lower extremity function. J. Am. Geriatr. Soc. 51, 1602–1609 (2003).

  23. 23.

    Vellas, B. et al. Mapt Study: a multidomain approach for preventing alzheimer’s disease: design and baseline data. J. Prev. Alzheimers Dis. 1, 13–22 (2014).

  24. 24.

    Kuba, K. et al. Impaired heart contractility in Apelin gene-deficient mice associated with aging and pressure overload. Circ. Res. 101, e32–e42 (2007).

  25. 25.

    Yamamoto, T. et al. Apelin-transgenic mice exhibit a resistance against diet-induced obesity by increasing vascular mass and mitochondrial biogenesis in skeletal muscle. Biochim. Biophys. Acta 1810, 853–862 (2011).

  26. 26.

    Wang, B. et al. Construction and analysis of compact muscle-specific promoters for AAV vectors. Gene Ther. 15, 1489–1499 (2008).

  27. 27.

    Tai, P. W. et al. Differentiation and fiber type-specific activity of a muscle creatine kinase intronic enhancer. Skelet. Muscle 1, 25 (2011).

  28. 28.

    Hauser, M. A. et al. Analysis of muscle creatine kinase regulatory elements in recombinant adenoviral vectors. Mol. Ther. 2, 16–25 (2000).

  29. 29.

    Katugampola, S. D., Maguire, J. J., Matthewson, S. R. & Davenport, A. P. [(125)I]-(Pyr(1))Apelin-13 is a novel radioligand for localizing the APJ orphan receptor in human and rat tissues with evidence for a vasoconstrictor role in man. Br. J. Pharmacol. 132, 1255–1260 (2001).

  30. 30.

    Pitkin, S. L., Maguire, J. J., Bonner, T. I. & Davenport, A. P. International Union of Basic and Clinical Pharmacology. LXXIV. Apelin receptor nomenclature, distribution, pharmacology, and function. Pharmacol. Rev. 62, 331–342 (2010).

  31. 31.

    Yang, P. et al. Elabela/toddler is an endogenous agonist of the apelin APJ receptor in the adult cardiovascular system, and exogenous administration of the peptide compensates for the downregulation of its expression in pulmonary arterial hypertension. Circulation 135, 1160–1173 (2017).

  32. 32.

    Medhurst, A. D. et al. Pharmacological and immunohistochemical characterization of the APJ receptor and its endogenous ligand apelin. J. Neurochem. 84, 1162–1172 (2003).

  33. 33.

    Jia, Y. X. et al. Apelin protects myocardial injury induced by isoproterenol in rats. Regul. Pept. 133, 147–154 (2006).

  34. 34.

    Chun, H. J. et al. Apelin signaling antagonizes Ang II effects in mouse models of atherosclerosis. J. Clin. Invest. 118, 3343–3354 (2008).

  35. 35.

    Jacobs, R. A. et al. Fast-twitch glycolytic skeletal muscle is predisposed to age-induced impairments in mitochondrial function. J. Gerontol. A Biol. Sci. Med. Sci. 68, 1010–1022 (2013).

  36. 36.

    Demontis, F., Piccirillo, R., Goldberg, A. L. & Perrimon, N. Mechanisms of skeletal muscle aging: insights from Drosophila and mammalian models. Dis. Model. Mech. 6, 1339–1352 (2013).

  37. 37.

    Stewart, V. H., Saunders, D. H. & Greig, C. A. Responsiveness of muscle size and strength to physical training in very elderly people: a systematic review. Scand. J. Med. Sci. Sports 24, e1–e10 (2014).

  38. 38.

    Pahor, M. et al. Effect of structured physical activity on prevention of major mobility disability in older adults: the LIFE study randomized clinical trial. JAMA 311, 2387–2396 (2014).

  39. 39.

    Westerblad, H. & Allen, D. G. Emerging roles of ROS/RNS in muscle function and fatigue. Antioxid. Redox Signal. 15, 2487–2499 (2011).

  40. 40.

    Snijders, T. et al. A single bout of exercise activates skeletal muscle satellite cells during subsequent overnight recovery. Exp. Physiol. 97, 762–773 (2012).

  41. 41.

    Allen, D. G., Lamb, G. D. & Westerblad, H. Skeletal muscle fatigue: cellular mechanisms. Physiol. Rev. 88, 287–332 (2008).

  42. 42.

    Masri, B., Morin, N., Cornu, M., Knibiehler, B. & Audigier, Y. Apelin (65–77) activates p70 S6 kinase and is mitogenic for umbilical endothelial cells. FASEB J. 18, 1909–1911 (2004).

  43. 43.

    Xie, F. et al. Apelin-13 promotes cardiomyocyte hypertrophy via PI3K–Akt–ERK1/2–p70S6K and PI3K-induced autophagy. Acta Biochim. Biophys. Sin. (Shanghai) 47, 969–980 (2015).

  44. 44.

    García-Prat, L., Sousa-Victor, P. & Muñoz-Cánoves, P. Functional dysregulation of stem cells during aging: a focus on skeletal muscle stem cells. FEBS J. 280, 4051–4062 (2013).

  45. 45.

    Lukjanenko, L. et al. Loss of fibronectin from the aged stem cell niche affects the regenerative capacity of skeletal muscle in mice. Nat. Med. 22, 897–905 (2016).

  46. 46.

    Pahor, M. et al. Effects of a physical activity intervention on measures of physical performance: results of the lifestyle interventions and independence for Elders Pilot (LIFE-P) study. J. Gerontol. A Biol. Sci. Med. Sci. 61, 1157–1165 (2006).

  47. 47.

    Papachristou, E. et al. The relationships between body composition characteristics and cognitive functioning in a population-based sample of older British men. BMC Geriatr. 15, 172 (2015).

  48. 48.

    Rai, R. et al. Downregulation of the apelinergic axis accelerates aging, whereas its systemic restoration improves the mammalian healthspan. Cell Rep. 21, 1471–1480 (2017).

  49. 49.

    Attané, C. et al. Apelin stimulates glucose uptake but not lipolysis in human adipose tissue ex vivo. J. Mol. Endocrinol. 46, 21–28 (2011).

  50. 50.

    Zhang, H. et al. Apelin inhibits the proliferation and migration of rat PASMCs via the activation of PI3K/Akt/mTOR signal and the inhibition of autophagy under hypoxia. J. Cell. Mol. Med. 18, 542–553 (2014).

  51. 51.

    Paturi, S. et al. Effects of aging and gender on muscle mass and regulation of Akt–mTOR–p70s6k related signaling in the F344BN rat model. Mech. Ageing Dev. 131, 202–209 (2010).

  52. 52.

    Sandri, M. et al. Signalling pathways regulating muscle mass in ageing skeletal muscle: the role of the IGF1–Akt–mTOR–FoxO pathway. Biogerontology 14, 303–323 (2013).

  53. 53.

    Ambrose, C. Muscle weakness during aging: a deficiency state involving declining angiogenesis. Ageing Res. Rev. 23(Pt B), 139–153 (2015).

  54. 54.

    Minetti, G. C. et al. Gαi2 signaling is required for skeletal muscle growth, regeneration, and satellite cell proliferation and differentiation. Mol. Cell. Biol. 34, 619–630 (2014).

  55. 55.

    Bertrand, C. et al. Effects of dietary eicosapentaenoic acid (EPA) supplementation in high-fat fed mice on lipid metabolism and apelin/APJ system in skeletal muscle. PLoS One 8, e78874 (2013).

  56. 56.

    Yue, P. et al. Apelin is necessary for the maintenance of insulin sensitivity. Am. J. Physiol. Endocrinol. Metab. 298, E59–E67 (2010).

  57. 57.

    Son, J. S. et al. Effects of exercise-induced apelin levels on skeletal muscle and their capillarization in type 2 diabetic rats. Muscle Nerve 56, 1155–1163 (2017).

  58. 58.

    Dray, C. et al. The intestinal glucose–apelin cycle controls carbohydrate absorption in mice. Gastroenterology 144, 771–780 (2013).

  59. 59.

    Pedersen, B. K. & Fischer, C. P. Beneficial health effects of exercise—the role of IL-6 as a myokine. Trends Pharmacol. Sci. 28, 152–156 (2007).

  60. 60.

    Chandrasekaran, B. et al. Myocardial apelin production is reduced in humans with left ventricular systolic dysfunction. J. Card. Fail. 16, 556–561 (2010).

  61. 61.

    Castan-Laurell, I. et al. Effect of hypocaloric diet-induced weight loss in obese women on plasma apelin and adipose tissue expression of apelin and APJ. Eur. J. Endocrinol. 158, 905–910 (2008).

  62. 62.

    Mamchaoui, K. et al. Immortalized pathological human myoblasts: towards a universal tool for the study of neuromuscular disorders. Skelet. Muscle 1, 34 (2011).

  63. 63.

    McMahon, C. D. et al. Myostatin-deficient mice lose more skeletal muscle mass than wild-type controls during hindlimb suspension. Am. J. Physiol. Endocrinol. Metab. 285, E82–E87 (2003).

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We thank V. Minville, I. Castan-Laurell, A. Yart, B. Masri, and L. Casteilla for their fruitful discussions. We also specially thank all of the personnel of the ANEXPLO animal facility (Toulouse, France) and transcriptomic GeTQ plateform (Toulouse, France); J. Rouquette, head of the ITAV Imaging Service (Centre Pierre Potier, Toulouse, France); Federico S. and the NIHS flow cytometry facility (Lausanne, Switzerland). We thank J. Iacovani and J. Christensen for corrections to the article and M. Rossell for technical assistance. Mice deficient for AMPK activity (DN-AMPK) in skeletal muscles were kindly provided by the laboratory of M. J. Birnbaum (University of Pennsylvania Medical School, Philadelphia, USA). This work has been funded by INSERM (Institut National de la Santé et de la Recherche Médicale), the Région Occitanie and the Fondation de la Recherche Médicale (FRM). This project was supported in part by European funds (Fonds Européens de Développement Régional, FEDER), Toulouse Métropole, and the French Ministry of Research through the Investissement d’Avenir Infrastructures Nationales en Biologie et Santé program (ProFI, Proteomics French Infrastructure project, ANR-10-INBS-08).

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Author notes

  1. These authors jointly directed this work: Philippe Valet, Cedric Dray.


  1. Institut des Maladies Métaboliques et Cardiovasculaires, INSERM U1048, Université de Toulouse, Université Paul Sabatier, Toulouse, France

    • Claire Vinel
    • , Aurelie Batut
    • , Simon Deleruyelle
    • , Jean-Philippe Pradère
    • , Sophie Le Gonidec
    • , Alizée Dortignac
    • , Nancy Geoffre
    • , Ophelie Pereira
    • , Etienne Mouisel
    • , Fabien Pillard
    • , Philippe Valet
    •  & Cedric Dray
  2. Aging Department, Nestlé Institute of Health Sciences SA, Ecole Polytechnique Fédérale de Lausanne Innovation Park, Lausanne, Switzerland

    • Laura Lukjanenko
    • , Sonia Karaz
    • , Umji Lee
    •  & Jerome N. Feige
  3. Institut de Pharmacologie et de Biologie Structurale–CNRS, Université de Toulouse, Université Paul Sabatier, Toulouse, France

    • Mylène Camus
    • , Karima Chaoui
    •  & Odile Burlet-Schiltz
  4. Institut de Myologie, Université Pierre et Marie Curie, Paris 6 UM76, Univ. Paris 6/U974, UMR7215, CNRS, Pitié-Salpétrière–INSERM, UMRS 974, Paris, France

    • Anne Bigot
    •  & Vincent Mouly
  5. Institut des Technologies Avancées en Science du Vivant–USR3505 Centre Pierre Potier, Toulouse, France

    • Mathieu Vigneau
  6. Université de Montpellier, Institut National de la Recherche Agronomique, UMR866 Dynamique Musculaire et Métabolisme, Montpellier, France

    • Allan F. Pagano
    •  & Angèle Chopard
  7. Gérontopole Toulouse-Purpan UMR 1027, Toulouse, France

    • Sophie Guyonnet
    • , Matteo Cesari
    •  & Bruno Vellas
  8. Institute on Aging, College of Medicine, University of Florida, Gainesville, FL, USA

    • Marco Pahor


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C.D. and P.V. conceived the study. C.V., S.L.G., A.D., O.P. and S.D. performed all animal experiments. C.V., L.L., S.K., U.L. and J.F.N. designed, performed and analyzed the regeneration experiments. C.D., C.V. and J.-P.P. performed all the western blots. C.V., A.D., O.P. and N.G. performed all the transcriptomics. V.M. and A.B. provided human cells. A.B. performed all the culture cell experiments. B.V., M.C., M.P., F.P. and S.G. were involved in human samples collection and analysis. A.C. and A.F.P. performed the hindlimb unloading experiments. M.C., K.C. and O.S. designed and performed the HPLC experiments. M.V. analyzed muscle fiber composition. E.M. participated in performing the specific muscle contraction tests. C.D. supervised the design and execution of the study, interpreted the results and wrote the manuscript.

Competing interests

The authors declare no competing interests.

Corresponding author

Correspondence to Cedric Dray.

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